title: Cytotoxic and apoptosis-inducing activities of limonoids from the seeds of Azadirachta indica (neem).
abstract: Thirty-five limonoids, including 15 of the azadiradione type (1-15), five of the gedunin type (16-20), four of the azadirachtin type (21-24), nine of the nimbin type (25-33), and two degraded limonoids (34, 35), isolated from Azadirachta indica seed extracts, were evaluated for their cytotoxic activities against five human cancer cell lines. Seven compounds (3, 6, 7, 16, 18, 28, and 29) exhibited cytotoxic activity against one or more cell lines. Among these compounds, 7-deacetyl-7-benzoylepoxyazadiradione (7), 7-deacetyl-7-benzoylgeduin (18), and 28-deoxonimbolide (28) exhibited potent cytotoxic activity against HL60 leukemia cells with IC(50) values in the range 2.7-3.1 μM. Compounds 7, 18, and 28 induced early apoptosis in HL60 cells, observed by flow cytometry. Western blot analysis showed that compounds 7, 18, and 28 activated caspases-3, -8, and -9 in HL60 cells. This suggested that compounds 7, 18, and 28 induced apoptotic cell death in HL60 cells via both the mitochondrial- and the death receptor-mediated pathways. Futhermore, compound 7 was shown to possess high selective cytotoxicity for leukemia cells since it exhibited only weak cytotoxicity against a normal lymphocyte cell line (RPMI 1788).
authors.affiliation: College of Science and Technology, Nihon University, 1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishii
authors.forename: Taisuke
authors.initials: T
authors.lastname: Noto
authors.forename: Akitomo
authors.initials: A
authors.lastname: Takahashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Akihisa
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D031601:Azadirachta / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D036701:Limonins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D053218:Receptors, Death Domain / Q000187:drug effects; D012639:Seeds / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D036701:Limonins; D053218:Receptors, Death Domain; C479321:azadiradione; C062897:28-deoxonimbolide; C106014:gedunin; C008621:nimbin; C010329:azadirachtin